Chronic overwhelming infections by pathogens such as hepatitis B virus (HBV), human immunodeficiency virus (HIV), Human papilloma virus (HPV), Mycobacterium tuberculosis, Histoplasma spp. and Plasmodium spp. are associated with a deficiency in pathogen-specific immunity and an aberrant non-specific inflammatory response that is deleterious in causing collateral host cell damage. Whilst various treatment strategies have been developed over the years, they have had little impact.
Hepatitis B is a common disease with a worldwide distribution, with an estimated 280,000,000 as being carriers of HBV. Globally, HBV infection is most common in the developing countries of Southeast Asia, Africa and parts of South America, where vertical transmission to infants at an early age results in a high proportion of infected individuals becoming chronic carriers of HBV. Males acquiring HBV as infants have approximately a 40% chance of dying from cirrhosis or primary hepatocellular carcinoma as a result of chronic HBV infection. By contrast, females infected at birth have about a 15% chance of dying a similar death from chronic hepatitis B infection.
Hepatitis B infection remains difficult to treat despite several drugs now in clinical use, including interferon α2b (IFN α2b), IFN α2a, lamivudine, adefovir and entecavir. Treatment is either ineffective at the outset, or can become so by the emergence of drug resistant viruses. Existing drug regimens have also been known to suffer from being long-term, expensive and associated with undesirable side effects. For example, while lamivudine has been applied with some success in the treatment of HBV infection, it is associated with an increasing risk of resistance, which can be as high as 45-55% after the second year of treatment. Moreover, HBV cannot be completely eliminated from the liver under such therapy, so that reactivation of a HBV infection occurs in many cases even after cessation a treatment. When end-stage liver failure occurs in patients with chronic HBV infection, liver transplantation is the only alternative form of treatment. However, as HBV infection persists, the graft can become infected, thus limiting patient and graft survival.
Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) also represents a global health crisis, particularly in developing countries. The use of anti-retroviral drugs has significantly changed the expectancy and quality of life of HIV infected individuals. However, in spite of such anti-retroviral drug intervention, persistent immune activation, CD4 T cell and B cell decay and loss of immune function are only partially reverted. Patients are also at risk of non-AIDS defining illnesses and causes of death, such as cancer, cardiovascular disease, liver and kidney failure, central nervous system disorders (e.g., toxoplasma encephalitis) and persistent infections.
The present invention is concerned with the development of a novel approach to the treatment of intracellular infections.